Project 3: Psychosis Abstract: A more severe phenotype of Alzheimer disease (AD) is identified by the occurrence of psychosis. AD with psychosis (AD+P) is common, with a cumulative incidence of ~ 40%-60% in subjects with AD. AD+P subjects have more rapid cognitive decline, increased disability, and greater mortality than AD subjects without psychosis (AD-P). Current empiric treatments for psychosis in AD have limited efficacy and are associated with substantial toxicity, motivating efforts to identify the underlying neurobiology of AD+P. We have assembled a large brain tissue collection of AD cases characterized antemortem for psychosis, placing us in a unique position to address this need. This project will test our overarching model that AD+P results from specific biologic processes that modify AD-related neurodegeneration, yielding more rapid cognitive decline and psychotic symptoms. This model initially derived from our observation that the occurrence of psychosis in AD is familial, a finding which has since been replicated in two independent cohorts. Brain imaging and neuropathologic studies provide further evidence of a characteristic neurobiology of AD+P, with exaggerated reductions of gray matter volume, blood flow, glucose metabolism, and increased phosphotau (pTau) burden in multiple neocortical regions. Additional AD+P risk may also result from comorbid neocortical stage Lewy body pathology. Nevertheless, in our preliminary data, after accounting for all of these pathologies, unexplained causation of psychosis in AD remains. The more rapid cognitive decline in AD+P, and observations that synapse loss is the strongest correlate of cognitive impairment, suggest that synaptic dysfunction and loss is one source of the missing neuropathology in AD+P. Additionally, recent genetic studies have highlighted inflammation as having a more central role in AD neurodegeneration than previously appreciated, and inflammation, especially when affecting synaptic proteins, is strongly associated with psychosis. We therefore propose a set of specific aims designed to determine the proportion of AD+P explained by these pathologies: 1) To quantify the burden of AD and comorbid neuropathologies within neocortical regions in AD+P and AD-P subjects; 2) To evaluate markers of synaptic dysfunction and loss in AD+P; 3) To evaluate markers of inflammation in AD+P. Combining a Sr. Investigator (Sweet) with expertise in the synaptic pathology of psychosis and a Jr. Investigator (Kofler) with expertise in the neuropathology and immunology of AD provides strong scientific synergy, increased likelihood of success, and an opportunity for career development. Completion of these aims will provide the necessary basis for future mechanistic studies assessing whether interventions to alter affected pathways (pTau, synaptic signaling & inflammatory) may slow synaptic impairment and cognitive decline downstream of A? in model systems. In addition, our findings will inform how much each pathologic process contributes to AD+P risk, and allow evaluation of whether that weighting differs across individuals, which could be important for future efforts at personalized therapeutics.